VCV000221271.29 - ClinVar

NM_001009994.3(RIPPLY2):c.238A>T (p.Arg80Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(2); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001009994.3(RIPPLY2):c.238A>T (p.Arg80Ter)

Variation ID: 221271 Accession: VCV000221271.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q14.2 6: 83854160 (GRCh38) [ NCBI UCSC ] 6: 84563879 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 9, 2016	Oct 20, 2024	Oct 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001009994.3:c.238A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001009994.1:p.Arg80Ter	nonsense
NM_001400774.1:c.-29A>T		5 prime UTR
NM_001400899.1:c.301A>T	NP_001387828.1:p.Arg101Ter	nonsense
NM_001400900.1:c.238A>T	NP_001387829.1:p.Arg80Trp	missense
NR_103525.2:n.233A>T		non-coding transcript variant
NR_174603.1:n.233A>T		non-coding transcript variant
NR_174604.1:n.295A>T		non-coding transcript variant
NR_174622.1:n.233A>T		non-coding transcript variant
NC_000006.12:g.83854160A>T
NC_000006.11:g.84563879A>T
NG_046722.1:g.5895A>T

... more HGVS ... less HGVS

Protein change

R80*, R101*, R80W

Other names

Canonical SPDI

NC_000006.12:83854159:A:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00012

The Genome Aggregation Database (gnomAD), exomes 0.00012

Trans-Omics for Precision Medicine (TOPMed) 0.00019

The Genome Aggregation Database (gnomAD) 0.00024

Links

ClinGen: CA351422 OMIM: 609891.0001 dbSNP: rs201419367 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RIPPLY2		-	-	GRCh38 GRCh37	2	95
RIPPLY2-CYB5R4	-	-	-	GRCh38	-	100

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Spondylocostal dysostosis 6, autosomal recessive	Pathogenic (2)	criteria provided, single submitter	Dec 5, 2022	RCV000207268.3
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Oct 6, 2023	RCV000275086.27
Spondylocostal dysostosis 2, autosomal recessive	not provided (1)	no classification provided	-	RCV002270021.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Dec 08, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000337717.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RIPPLY2 Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Dec 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spondylocostal dysostosis 6, autosomal recessive Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003834817.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Uncertain significance (Oct 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003515263.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 25343988 Comment: This sequence change creates a premature translational stop signal (p.Arg80) in the RIPPLY2 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Arg80) in the RIPPLY2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the RIPPLY2 protein. This variant is present in population databases (rs201419367, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with multiple segmentation defects (PMID: 25343988). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 221271). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Pathogenic (Jun 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002545437.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: RIPPLY2: PVS1:Strong, PM2, PM3, PP4, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (Mar 01, 2015)	no assertion criteria provided Method: literature only	SPONDYLOCOSTAL DYSOSTOSIS 6, AUTOSOMAL RECESSIVE (1 family) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000262593.1 First in ClinVar: Feb 09, 2016 Last updated: Feb 09, 2016	Publications: PubMed (1) PubMed: 25343988 Comment on evidence: In 2 brothers (family SKDP-10) with segmentation defects of the vertebrae (SCDO6; 616566), McInerney-Leo et al. (2015) identified compound heterozygosity for 2 mutations in the … (more) In 2 brothers (family SKDP-10) with segmentation defects of the vertebrae (SCDO6; 616566), McInerney-Leo et al. (2015) identified compound heterozygosity for 2 mutations in the RIPPLY2 gene: a c.238A-T transversion (c.238A-T, NM_001009994) in exon 3 of the RIPPLY2 gene, resulting in an arg80-to-ter (R80X) substitution, and a c.240-4T-G transversion in intron 3 (609891.0002) at the 5-prime predicted splice acceptor site for exon 4. Their unaffected parents were each heterozygous for 1 of the mutations, as was the unaffected maternal grandmother, whereas their unaffected sister did not carry either of the mutations. McInerney-Leo et al. (2015) noted that the R80X mutation causes loss of 49 C-terminal amino acids, including the highly conserved Ripply homology domain required for direct protein-protein interaction with the T-box domain of TBX6 (602427). Functional analysis in transiently transfected C2C12 mouse myoblasts demonstrated significantly reduced transcriptional repression activity with the R80X mutant compared to wildtype RIPPLY2. The authors stated that they were unable to demonstrate a functional consequence of the c.240-4T-G mutation because of its location in the terminal exon splice site consensus sequence and the likely restriction of RIPPLY2 expression to embryogenesis. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807180.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959299.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: literature only	Spondylocostal dysostosis 2, autosomal recessive Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV002555542.2 First in ClinVar: Jul 30, 2022 Last updated: Oct 01, 2022	Publications: BookShelf: NBK8828 BookShelf: NBK8828

Comment:

This sequence change creates a premature translational stop signal (p.Arg80*) in the RIPPLY2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the RIPPLY2 protein. This variant is present in population databases (rs201419367, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with multiple segmentation defects (PMID: 25343988). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 221271). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Spondylocostal Dysostosis, Autosomal Recessive.	Adam MP	-	2023	PMID: 20301771
Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects.	McInerney-Leo AM	Human molecular genetics	2015	PMID: 25343988
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RIPPLY2	-	-	-	-

Text-mined citations for rs201419367 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001009994.3(RIPPLY2):c.238A>T (p.Arg80Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201419367 ...